Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. Schizophrenia is thought to be due to an imbalance of dopamine in certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of prolonged depression and apathy similar to the negative symptoms seen in schizophrenics. Similarly, in rats the repeated administration of high doses of cocaine can produce a decrease in locomotor activity and a lack of the usual sensitization state seen with lower dose stimulant drug challenge. In earlier studies, we evaluated the effects of cocaine on the activity of tyrosine hydroxylase in five brain regions of rats. Cocaine administered in a dose of 10 mg/kg intraperitoneally, given twice a day for seven days produced a significant increase in tyrosine hydroxylase activity of approximately 50% in the ventral tegmental area at six and 12 weeks after the last cocaine administration. Similar studies have been performed measuring the in vivo hydroxylation of tyrosine in these brain regions. Cocaine produced a significant decrease in tyrosine hydroxylation in the frontal cortex (30%) and nucleus accumbens (34%) compared with saline treated rats six weeks after the last injection. The cocaine-induced increase in tyrosine hydroxylase activity in the ventral tegmental area was prevented by the NMDA antagonist, MK-801, and the dopamine D2 antagonists, haloperidol and clozapine. The D1 receptor antagonist, SCH23390 had no significant effect on the increase in tyrosine hydroxylase activity, and SCH23390 alone enhanced tyrosine hydroxylase activity.